Pharmacokinetics - Metabolism Flashcards
3 major routes involved in elimination:
- Hepatic Metabolism
- Elimination in bile
- Elimination in urine
What is clearance?
Clearance (CL) estimates the amount of drug cleared from the body per unit of time
How is total clearance calculated?
CL = 0.693 × Vd
_____
t1/2
Give Michaelis-Menten Equation for 1st order kinetics
v = rate of drug metabolism= V max (C)
—————-
Km
What is first order kinetics?
The rate of drug metabolism and elimination is directly proportional to the concentration of free drug
First-order kinetics is sometimes referred to clinically as __________
linear kinetics
In First Order Kinetics, with every half-life the
concentration reduces by ______.
50%
Give Michaelis-Menten Equation for zero order kinetics
v = rate of drug metabolism = Vmax
Give drugs that show zero order kinetics.
aspirin, ethanol , phenytoin
the doses are very large
What is zero order kinetics?
The enzyme is saturated by a high free-drug concentration, and the rate of metabolism remains constant over time.
Zero-order kinetics is sometimes referred to clinically as __________
Non-linear kinetics
The ______ cannot efficiently eliminate lipophilic drugs that readily cross cell membranes and are reabsorbed in the distal convoluted tubules
kidney
Lipid-soluble agents must first be metabolized into
more _______ substances in the liver using two general sets of reactions, called Phase I and Phase II
polar (hydrophilic)
_________ reactions convert lipophilic molecules into more polar molecules by introducing or unmasking a polar functional group, such as –OH or –NH2.
Phase I
Phase I metabolism may have which effect on the drug’s pharmacologic activity?
a. increase
b. decrease
c. leave unaltered
d. All of the above
d. All of the above
The Phase I reactions most frequently involved in drug metabolism are catalyzed by the ______system
cytochrome P450
cytochrome P450 is also called _______
microsomal mixed-function oxidases
The P450 system is important for:
- The metabolism of many endogenous compounds (such as steroids, lipids, etc.
- The biotransformation of exogenous substances (xenobiotics)
Cytochrome P450, designated as CYP, is a superfamily of ________that are located in most cells but are
primarily found in the liver and GI tract.
heme-containing isozymes
Define nomenclature for Cytochrome P450 enzymes.
The family name is indicated by CYP added to
an arabic number, followed by a capital letter for the subfamily,
for example, CYP3A
Another number is added to indicate the specific isozyme, as in CYP3A4
There are many different P450 ______
isoforms
Four isozymes are responsible for the vast majority of P450-catalyzed reactions. They are :
CYP3A4/5
CYP2D6,
CYP2C8/9,
and CYP1A2
Considerable amounts of
______ are found in intestinal mucosa, accounting for the first-pass metabolism of drugs such as chlorpromazine and clonazepam.
CYP3A4
P450 enzymes exhibit considerable
genetic variability among individuals and ______
racial groups
______, in particular, has been
shown to exhibit genetic polymorphism
CYP2D6
_______ mutations result in very low capacities to metabolize substrates
CYP2D6
Patients who are poor CYP2C19 metabolizers
have a higher incidence of cardiovascular events (for example, stroke or myocardial infarction) when taking _________
clopidogrel
Clopidogrel is a ______ and CYP2C19 activation is required to convert it to its (active) metabolite
Prodrug
no polymorphisms have been identified so far for this P450 isozyme.
CYP3A4
Some individuals obtain no benefit from the opioid analgesic codeine, because they lack the _____enzyme that O-demethylates and activates the drug
CYP2D6
The frequency of CYP2D6 polymorphism is in part racially determined.
It’s prevalence in European Caucasians is:
It’s prevalence in Southeast Asians is:
5 to 10 % in European Caucasians
Less than 2% in Southeast Asians
Isozyme CYP 2C9/10 Substrate drugs:
Warfarin
Phenytoin
Ibuprofen
Tolbutamide
Isozyme CYP 2C9/10 Inducers:
Phenobarbital
Rifampin
Isozyme CYP 2D6 Substrate drugs:
Desipramine
Imipramine
Haloperidol
Propranolol
Isozyme CYP 3A4/5 Substrate drugs:
Carbamazepine Cyclosporine Erythromycin Clarithromycin Nifedipine Verapamil Simvastatin
Isozyme CYP 3A4/5 Inducers:
Carbamazepine Dexamethasone Phenobarbital Phenytoin Rifampin
What are CYP Isozyme Inducers:
Certain drugs are capable of increasing the synthesis of one or more CYP isozymes.
This results in increased biotransformation of drugs
and significant decreases in plasma concentrations, with concurrent loss of pharmacologic effect.
Rifampin, an antituberculosis drug, significantly decreases the plasma concentrations of_________.
HIV protease inhibitors
HIV protease inhibitors role:
suppress HIV virion maturation
Omeprazole is a potent inhibitor of three of the CYP
isozymes responsible for ______ metabolism
warfarin
If the Omeprazole and Warfarin are taken together:
Plasma concentrations of warfarin increase,
which leads to greater inhibition of coagulation and risk of hemorrhage and other serious bleeding reactions.
Name important CYP inhibitors:
erythromycin
ketoconazole,
ritonavir
(because they each inhibit several CYP isozymes)
_____ blocks the metabolism of theophylline, clozapine and warfarin
Cimetidine
Why Grapefruit is contraindicated with Simvastatin?
Grapefruit and its juice inhibits CYP3A4.
Drugs such as nifedipine, clarithromycin, and simvastatin, are metabolized by this system,
(higher blood levels and the potential to increase the drugs’ therapeutic and/or toxic effects)
Phase I reactions not involving the P450 system:
- Amine oxidation e.g. oxidation of catecholamines or
histamine - Alcohol dehydrogenation e.g. ethanol
oxidation - Esterases e.g. metabolism of pravastatin in
liver - Hydrolysis e.g. of procaine
Phase II consists of ______ reactions
conjugation
If the metabolite from Phase I metabolism is sufficiently ______, it can be excreted by the kidneys.
Polar
Conjugation reaction with the following groups results in polar, usually more water-soluble compounds that are most often therapeutically inactive.
glucuronic acid
sulfuric acid
acetic acid
amino acid
_________is the most common and the most important conjugation reaction
Glucuronidation
Glucuronidation renders the drug inactive. A notable exception to glucuronidation is :
morphine-6-glucuronide ,
which is more potent than morphine
_______ are deficient in this conjugating system
Neonates
Why Chloramphenicol is not given to neonates?
chloramphenicol is inactivated by the
addition of glucuronic acid.
Since Neonates are deficient in this conjugating system, it results in gray baby syndrome.
Drugs already possessing these groups may enter Phase II directly and become conjugated without prior Phase I metabolism
–OH, –NH2, or –COOH
The highly polar drug conjugates may be excreted by :
the kidney or in bile
Not all drugs undergo Phase I and
II reactions in that order. Give example
Isoniazid is first acetylated (a Phase II reaction) and then hydrolyzed to isonicotinic acid (a Phase I reaction)
